An estimated 25% of infants in this country are exposed prenatally to drugs of abuse, a significant proportion of which are illicit drugs. Furthermore, a significant number of newborn infants, many of them premature, are exposed to opioids for pain relief following surgical or traumatic events, the long-term consequences for which are little understood. Beyond well documented developmental disabilities, the possibility that individuals exposed to drugs of abuse early in life are rendered more likely to abuse drugs as adults is a particularly alarming prospect, and has been suggested in a number of clinical studies. A critical role for glial cells (e.g., microglia, astrocytes) in addiction is becoming increasingly apparent. For instance, it has recently been demonstrated that morphine and cocaine directly activate glial cells within the CNS in a non-classical opioid receptor manner, via the innate immune system's pattern recognition receptor, toll-like receptor (TLR) 4, and, in the case of morphine, that this glial activation contributes strongly to their rewarding properties. Thus, glial inhibitors or selective TLR4 antagonists markedly reduce opioid-induced dependence, tolerance, and reward. In infants, glial cells are critical for many aspects of normal brain development, including apoptosis, axonal growth, angiogenesis, and synaptogenesis. As the primary "immuno-competent" cells of the brain, they also respond vigorously to virtually any disturbance of homeostasis, such as injury or infection, and this activation may cause long-term alterations in their function. This proposal has been designed to test the hypothesis that events occurring during the perinatal period of life often produce enduring effects on brain and behavior, including abuse liability later in life, via their influence on glial cell activity and subsequent neural development. This hypothesis will be tested by examining the following questions, using gene expression, protein expression, pharmacological and behavioral techniques: (1) What is the impact of perinatal exposure to morphine and cocaine on glial and neural cell development and function? (2) What is the role for alterations in glial cell development and/or function in later life abuse liability? and (3) Will attenuating glial activation early in life protect from increased abuse liability in adulthood? These collective data will provide novel insight into the role that early life noxious events, including drug exposure, have on neural and glial cell development within the CNS, as well as the role that glial cells play in substance abuse at a behavioral and pharmacological level. PUBLIC HEALTH RELEVANCE: An estimated 25% or more of infants in this country are exposed prenatally to drugs of abuse, and a significant number of newborn infants, many of them premature, are exposed to opioids for pain relief following surgical or traumatic events, the long-term consequences for which are little understood. A critical role for glial cells (e.g., microglia, astrocytes) in addiction is becoming increasingly apparent. The data collected from this proposal will provide novel insight into the role that early life noxious events, including drug exposure, have on neural and glial cell development within the CNS, the role that glial cells play in substance abuse at a behavioral and pharmacological level, and ultimately treatment decisions.